Polymeric monomer of polytheanine, preparation method of polymeric monomer, polytheanine and preparation method of polytheanine

Abstract

The invention belongs to the technical field of polyamino acid, and provides a polymeric monomer of polytheanine, a preparation method of the polymeric monomer, the polytheanine and a preparation method of the polytheanine. The polymeric monomer of the poly-theanine with the structure as shown in the formula I is theanine-N-thiocarboxylic anhydride (The-NTA), and the poly-theanine can be synthesized through an NTA ring opening polymerization method; the polymeric monomer of the poly-theanine with the structure as shown in the formula II is N-phenoxycarbonyl theanine (The-NPC), and the poly-theanine can be synthesized by using an NPC polymerization method. According to the polymeric monomer provided by the invention, harsh conditions for synthesizing polytheanine by an existing amino acid-N-carboxylic anhydride (NCA) ring-opening polymerization method are avoided, so that conditions for preparing polytheanine are mild.

Description

Technical Field

[0001] The present invention relates to the technical field of polyamino acids, and particularly relates to a polymerization monomer of polytheanine, a preparation method thereof, polytheanine and a preparation method thereof. Background Art

[0002] Poly(α-amino acid)s (PAA) are macromolecular compounds formed by connecting amino acids as repeating units through peptide bonds, and have excellent biocompatibility and biodegradability. Due to the rich structure of the side chain R group of PAA, it exhibits rich physical and chemical properties. For example, polylysine (PLys) and polyglutamic acid (PGlu) have pH responsiveness, polyalanine (PAla) and polyphenylalanine (PPhe) show oil solubility, while polyserine (PSer) and polyglycine (PSar) have good water solubility. With these unique properties, PAA shows broad application prospects in biomedical fields such as drug delivery, gene transfection, biosensors, and tissue engineering.

[0003] Currently, the chemical synthesis methods of polyamino acids mainly include: solid-phase synthesis method (mainly used for oligopeptide synthesis), amino acid- N -carboxylic anhydride (NCA) ring-opening polymerization method, amino acid- N -thio-carboxylic anhydride (NTA) ring-opening polymerization method and N -phenoxycarbonyl amino acid (NPC) polymerization method.

[0004] Theanine (N-ethyl-γ-glutamine) has the following structure: .

[0005] Theanine belongs to the derivatives of glutamine and is a natural non-protein amino acid, which is widely present in tea. Research shows that theanine has various physiological activities such as neuroprotection, anti-fatigue, anti-tumor, and blood pressure lowering, and has important application value in the fields of food, medicine, chemical industry, etc. Polytheanine (PThe) is a kind of polyamino acid with amide groups in the side chain. Currently, the research on its synthesis and application is still in the initial stage. At present, some researchers have tried to prepare polytheanine by electrochemical polymerization method, but failed to successfully isolate the target product for systematic characterization of its structure and properties (J. Electroanal. Chem., 2013, 709, 1-9). In the same year, the researchers proposed a new method, that is, directly synthesizing amino acid- N-carboxylic anhydride NCA monomers, and preparing the corresponding polyamino acids by ring-opening polymerization (Japanese Patent JP 2013-234207 A, November 21, 2013); however, NCA monomers have extremely high reactivity, and strict anhydrous and anaerobic conditions are required during the synthesis, purification, storage, and polymerization reaction to form theanine, which greatly limits the feasibility of its large-scale production. Summary of the Invention

[0006] In view of this, the object of the present invention is to provide a polymerization monomer of theanine, a preparation method thereof, theanine, and a preparation method thereof. The polymerization monomer provided by the present invention can make the preparation conditions of theanine mild.

[0007] To achieve the above object of the invention, the present invention provides the following technical solutions: The present invention provides a polymerization monomer of theanine having a structure represented by Formula I or Formula II: Formula I, Formula II.

[0008] The present invention also provides a preparation method of the polymerization monomer of theanine according to the above technical solution. The preparation method of the structure represented by Formula I includes the following steps: Mix theanine, S-ethoxycarbonylthioacetic acid, a base, and water, and carry out a nucleophilic substitution reaction to obtain an N-ethoxycarbonyltheanine intermediate; The N-ethoxycarbonyltheanine intermediate undergoes a ring-closing reaction under the condition of phosphorus tribromide to obtain the structure represented by Formula I; The preparation method of the structure represented by Formula II includes the following steps: Theanine, phenyl chloroformate, and sodium bicarbonate undergo an elimination reaction in a two-phase mixed solvent to obtain the structure represented by Formula II; the two-phase mixed solvent includes water and an organic solvent.

[0009] Preferably, during the nucleophilic substitution reaction, theanine is L-theanine; the base includes one or more of inorganic bases and / or organic bases; The inorganic base includes sodium hydroxide and / or potassium hydroxide; The organic base includes one or more of sodium alkoxide, potassium alkoxide, and tetraalkylammonium hydroxide; The number of carbon atoms of the sodium alkoxide and potassium alkoxide is independently 1-4; The number of carbon atoms of the alkyl group in the tetraalkylammonium hydroxide is 2-8; The molar ratio of theanine to S-ethoxycarbonylthioacetic acid is 1-2:1, and the molar ratio of theanine to the base is 1:2-4; The time of the nucleophilic substitution reaction is 12 to 120 h.

[0010] Preferably, during the ring-closing reaction, the molar ratio of the N-ethoxycarbonylthiocarbonyltheanine intermediate to phosphorus tribromide is 1:1 to 3, and the time of the ring-closing reaction is 3 h.

[0011] Preferably, during the elimination reaction, the theanine is L-theanine, the molar ratio of the theanine to phenyl chloroformate is 2:1 to 1:2, and the molar ratio of the theanine to sodium bicarbonate is 1:2 to 4; The organic solvent includes one or more of methyl tert-butyl ether, diethyl ether, ethyl acetate, dichloromethane, dichloroethane, and chloroform; The volume ratio of water to the organic solvent in the two-phase mixed solvent is 2:1 to 1:2; the temperature of the elimination reaction is 15 to 35 °C, and the time is 3 to 24 h.

[0012] The present invention also provides a polytheanine having the structure shown in Formula III: Formula III; In Formula III, R1 is one or more of an alkyl group, a benzyl group, a silicon group, a polyamino acid chain, a polyether chain, or a polyamide chain; R2 is hydrogen, a silicon group, or a C1-C8 alkyl group; R3 is hydrogen.

[0013] The present invention also provides a preparation method of the polytheanine described in the above technical solution, including the following steps: Mix the polymerization monomer, initiator, and polar solvent of the polytheanine, and carry out a polymerization reaction to obtain the polytheanine; The polymerization monomer of the polytheanine is the polymerization monomer of the polytheanine described in the above technical solution; The initiator is one or more of a primary aliphatic amine, a secondary aliphatic amine, benzylamine, silylamine, polyamino acid, polyetheramine, or polyamide.

[0014] Preferably, the molar ratio of the polymerization monomer to the initiator of the polytheanine is 5 to 200:1.

[0015] Preferably, the polar solvent includes one or more of dioxane, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, sulfolane, acetonitrile, benzonitrile, dichloromethane, dichloroethane, chloroform, toluene, acetone, methanol, ethanol, ethylene glycol, and water.

[0016] Preferably, the temperature of the first polymerization reaction is 20 to 100 °C, and the time is 0.5 to 72 h.

[0017] The present invention provides a polymerization monomer of theaamino acid, which has the structures shown in Formula I and Formula II.

[0018] The monomer with the structure shown in Formula I provided by the present invention is theanine- N -thioanhydride (The-NTA), and polytheanine can be synthesized by the ring-opening polymerization method of NTA; the monomer with the structure shown in Formula II is N -phenoxycarbonyl theanine (The-NPC), and polytheanine can be synthesized by using the NPC polymerization method. Compared with the common NCA monomers, the polymerization monomers The-NTA and The-NPC provided by the present invention have better nucleophile tolerance, higher storage stability and better polymerization operability. At the same time, the polymerization monomers of the present invention are more stable under the conditions of water, oxygen and heat. The synthesis process does not require complex protection measures and can directly carry out the polymerization reaction, significantly simplifying the synthesis process. In addition, the two polymerization monomers of the present invention can be further copolymerized with various different types of amino acid-NTA or amino acid-NPC monomers to obtain polyamino acids with various structures and functions. The polymerization monomers provided by the present invention avoid the harsh conditions of the existing NCA ring-opening polymerization method for synthesizing polytheanine, making the conditions for preparing polytheanine mild.

[0019] The present invention also provides a preparation method of the polymerization monomer of theaamino acid described in the above technical solution. The preparation method provided by the present invention can be formed under the condition of containing water without the need to carry out under the anhydrous and anaerobic conditions, and the reaction conditions are mild.

[0020] The present invention also provides a preparation method of theaamino acid described in the above technical solution. The preparation method of the present invention uses the polymerization monomers with the structures shown in Formula I and Formula II to prepare theaamino acid. The molecular weight of the theaamino acid prepared by the present invention is controllable and the molecular weight distribution is narrow; the composition of theaamino acid is adjustable and the content of theanine residues is adjustable; more importantly, the theaamino acid has excellent adjustable properties, such as water solubility, oil solubility, processing properties, etc., so that it can adapt to different application scenarios and has broad application potential. Description of the Drawings

[0021] Figure 1 1H NMR spectrum of The-NTA in Example 1; 1 H NMR spectrum; Figure 2 1H NMR spectrum of The-NPC in Example 2; 1 H NMR spectrum; Figure 3 1H NMR spectrum of theaamino acid in Example 3; 1 H NMR spectrum; Figure 4 Optical photograph of the aqueous solution of theaamino acid (150 mg / mL) in Example 4; Figure 5 For the 1H NMR spectrum of poly(sarcosine)- b -poly(theanine) in Example 9 1 H NMR spectrum. Detailed implementation mode

[0022] The present invention provides a polymerization monomer of theanine, having the structure shown in Formula I or Formula II: Formula I, Formula II.

[0023] In the present invention, Formula I is theanine- N -thiosuccinic anhydride (The-NTA). In the present invention, Formula II is N -phenoxycarbonyl theanine (The-NPC).

[0024] In the present invention, the The-NTA may have optical isomers, including L-type, D-type or racemic mixture (DL type).

[0025] In the present invention, the The-NPC may have optical isomers, including L-type, D-type or racemic mixture (DL type).

[0026] Compared with common NCA monomers, the polymerization monomers The-NTA and The-NPC of the present invention have better nucleophile tolerance, higher storage stability and better polymerization operability. At the same time, the polymerization monomers of the present invention are more stable under water, oxygen and heat conditions, and complex protection measures are not required in the synthesis process, and the polymerization reaction can be directly carried out, significantly simplifying the synthesis process of forming theanine by polymerization reaction.

[0027] The present invention also provides a preparation method of the polymerization monomer of theanine described in the above technical solution. The preparation method of the structure shown in Formula I includes the following steps: Mix theanine, S-ethoxycarbonylthioacetic acid, base and water, and carry out a nucleophilic substitution reaction to obtain an N-ethoxycarbonyl theanine intermediate; The N-ethoxycarbonyl theanine intermediate undergoes a ring-closing reaction under the condition of phosphorus tribromide to obtain the structure shown in Formula I; The preparation method of the structure shown in Formula II includes the following steps: Theanine, phenyl chloroformate and sodium bicarbonate undergo an elimination reaction in a two-phase mixed solvent to obtain the structure shown in Formula II; The two-phase mixed solvent includes water and an organic solvent.

[0028] Unless otherwise specified, the raw materials used in the present invention are preferably commercially available products.

[0029] In the present invention, the preparation method of the structure represented by Formula I includes the following steps: mixing L-theanine, S-ethoxycarbonyl mercaptoacetic acid, a base and water, and performing a nucleophilic substitution reaction to obtain an N-ethoxycarbonyl theanine intermediate; the N-ethoxycarbonyl theanine intermediate undergoes a ring-closing reaction under the condition of phosphorus tribromide to obtain the structure represented by Formula I.

[0030] In the present invention, the L-theanine is preferably L-theanine, and using L-theanine as the raw material reduces the preparation cost. In the present invention, the base preferably includes one or more of inorganic bases and / or organic bases. In the present invention, the inorganic base preferably includes sodium hydroxide and / or potassium hydroxide. In the present invention, the organic base preferably includes one or more of sodium alkoxide, potassium alkoxide and tetraalkylammonium hydroxide. In the present invention, the number of carbon atoms of the sodium alkoxide and potassium alkoxide is independently preferably 1-4, specifically preferably sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium n-propoxide, potassium n-propoxide, sodium n-butoxide or potassium n-butoxide. In the present invention, the number of carbon atoms of the alkyl group in the tetraalkylammonium hydroxide is preferably 2-8, more preferably 2-4, specifically preferably tetraethylammonium hydroxide, tetrapropylammonium hydroxide or tetrabutylammonium hydroxide.

[0031] In the present invention, the molar ratio of the L-theanine to S-ethoxycarbonyl mercaptoacetic acid is preferably 1-2:1, specifically preferably 1:1, 1.5:1 or 2:1.

[0032] In the present invention, the molar ratio of the L-theanine to the base is preferably 1:2-4, specifically preferably 1:2, 1:3 or 1:4.

[0033] In the present invention, the mixing of the L-theanine, S-ethoxycarbonyl mercaptoacetic acid, the base and water preferably includes the following steps: dissolving the L-theanine and S S-ethoxycarbonyl mercaptoacetic acid in water, and then adding the base and stirring until dissolved. In the present invention, the addition of the base is preferably carried out under an ice-water bath condition. The present invention does not specifically limit the rotation speed and time of the stirring, as long as the base can be completely dissolved.

[0034] In the present invention, the temperature of the nucleophilic substitution reaction is preferably room temperature, that is, neither additional heating nor additional cooling is required; the time of the nucleophilic substitution reaction is preferably 12-120 h, specifically preferably 12 h, 24 h, 36 h, 48 h, 60 h, 72 h, 84 h, 96 h, 108 h or 120 h.

[0035] After the nucleophilic substitution reaction, the present invention preferably further includes: adjusting the pH value of the obtained nucleophilic substitution reaction liquid to acidic to obtain an acidified solution; extracting the acidified solution with ethyl acetate and combining the organic phases; washing, drying and concentrating the organic phases in sequence to obtain the N-ethoxycarbonylthio L-theanine intermediate. In the present invention, the pH value of the acidity is preferably 1-2, specifically preferably 1, 1.5 or 2. In the present invention, the reagent for washing is preferably an aqueous citric acid solution with a concentration of 5 wt%. In the present invention, the drying is preferably drying with a desiccant, and the desiccant is preferably anhydrous sodium sulfate. In the present invention, the concentration method is preferably rotary evaporation. The present invention does not specifically limit the parameters of the rotary evaporation as long as the solvent can be removed.

[0036] In the present invention, during the ring-closing reaction, the molar ratio of the N-ethoxycarbonylthio L-theanine intermediate to phosphorus tribromide is 1:1-3, specifically preferably 1:1, 1:1.2, 1:1.5, 1:2, 1:2.5 or 1:3.

[0037] In the present invention, the N-ethoxycarbonylthio L-theanine intermediate is preferably dissolved in ethyl acetate for the ring-closing reaction. In the present invention, phosphorus tribromide is preferably added under the condition of an ice-water bath.

[0038] In the present invention, the temperature of the ring-closing reaction is preferably room temperature, that is, neither additional heating nor additional cooling is required; the time of the ring-closing reaction is preferably 0.5-24 h, specifically preferably 0.5 h, 1 h, 2 h, 3 h, 6 h, 9 h, 12 h, 15 h, 18 h, 21 h or 24 h.

[0039] In the present invention, the N-ethoxycarbonylthio L-theanine intermediate undergoes a ring-closing reaction under the condition of phosphorus tribromide, which preferably includes the following steps: dissolving the N-ethoxycarbonylthio L-theanine intermediate in ethyl acetate to obtain an intermediate solution; adding phosphorus tribromide to the intermediate solution under the condition of an ice-water bath for the ring-closing reaction.

[0040] After the ring-closing reaction, the present invention preferably further includes: extracting the obtained ring-closing reaction liquid with saturated brine and collecting the organic phase; washing, drying, concentrating and recrystallizing the organic phase in sequence to obtain the structure shown in Formula I. In the present invention, the reagent for washing is preferably an aqueous saturated sodium bicarbonate solution. In the present invention, the drying is preferably drying with a desiccant, and the desiccant is preferably anhydrous sodium sulfate. In the present invention, the concentration method is preferably rotary evaporation. In the present invention, the reagent for recrystallization is preferably a mixed solvent of ethyl acetate and n-hexane, and the volume ratio of ethyl acetate to n-hexane in the mixed solvent of ethyl acetate and n-hexane is preferably 1:1-2, specifically preferably 1:1 or 1:2.

[0041] In the present invention, the preparation formula of the structure shown in Formula I is as shown in Formula 1: Formula 1.

[0042] In the present invention, the preparation method of the structure shown in Formula II includes the following steps: L-theanine, phenyl chloroformate and sodium bicarbonate are subjected to an elimination reaction in a two-phase mixed solvent to obtain the structure shown in Formula II; the two-phase mixed solvent includes water and an organic solvent.

[0043] In the present invention, the L-theanine is preferably L-theanine. In the present invention, the molar ratio of the L-theanine to phenyl chloroformate is preferably 2:1 to 1:2, specifically preferably 2:1, 1:1 or 1:2. In the present invention, the molar ratio of the L-theanine to sodium bicarbonate is preferably 1:2 to 4, specifically preferably 1:2, 1:3 or 1:4. In the present invention, the organic solvent preferably includes one or more of methyl tert-butyl ether, diethyl ether, ethyl acetate, dichloromethane, dichloroethane and chloroform. In the present invention, the volume ratio of water to the organic solvent in the two-phase mixed solvent is preferably 2:1 to 1:2, specifically preferably 2:1, 1:1 or 1:2.

[0044] In the present invention, the phenyl chloroformate is preferably added under the condition of an ice-water bath.

[0045] In the present invention, the temperature of the elimination reaction is preferably 15 to 35 °C, specifically preferably 15 °C, 20 °C, 25 °C, 30 °C or 35 °C, and the time is preferably 3 to 24 h, specifically preferably 3 h, 6 h, 9 h, 12 h, 15 h, 18 h, 21 h or 24 h. In the present invention, the elimination reaction is preferably carried out under stirring.

[0046] In the present invention, the L-theanine, phenyl chloroformate and sodium bicarbonate are subjected to an elimination reaction in a two-phase mixed solvent preferably including the following steps: mixing the L-theanine, sodium bicarbonate and water, and then successively adding the organic solvent and phenyl chloroformate to carry out the elimination reaction.

[0047] After the elimination reaction, the present invention preferably further includes: successively washing, acidifying, and extracting with ethyl acetate the obtained aqueous phase to obtain an organic phase; successively drying, rotary evaporating, and recrystallizing the organic phase to obtain the structure shown in Formula II. In the present invention, the reagent for washing is preferably an organic solvent, and the type of the organic solvent is preferably the same as the organic solvent in the two-phase mixed solvent, which will not be elaborated here. In the present invention, the reagent for acidifying is preferably hydrochloric acid, and the target pH value for acidification is preferably 1-2, specifically preferably 1 or 2. In the present invention, the drying is preferably drying with a desiccant, and the desiccant is preferably anhydrous sodium sulfate. In the present invention, the method of concentration is preferably rotary evaporation. In the present invention, the reagent for recrystallization is preferably a mixed solvent of ethyl acetate and n-hexane, and in the mixed solvent of ethyl acetate and n-hexane, the volume ratio of ethyl acetate to n-hexane is preferably 1:1-2, specifically preferably 1:1, 1:1.5, or 1:2.

[0048] In the present invention, the preparation formula of the structure shown in Formula II is as shown in Formula 2: Formula 2.

[0049] The present invention also provides a theanine having the structure shown in Formula III: Formula III; In Formula III, R1 is one or more of an alkyl group, a benzyl group, a silicon group, a polyamino acid chain, a polyether chain, or a polyamide chain; R2 is hydrogen, a silicon group, or a C1-C8 alkyl group; R3 is hydrogen.

[0050] In the present invention, in Formula III, R1 and R2 are from an initiator.

[0051] In the present invention, the alkyl group in R1 is specifically preferably methyl, ethyl, n-propyl, neopentyl, or n-hexyl. In the present invention, the silicon group in R1 is specifically preferably trimethylsilyl.

[0052] In the present invention, the C1-C8 alkyl group in R2 is specifically preferably methyl, ethyl, n-propyl, neopentyl, or n-hexyl. In the present invention, the silicon group in R2 is specifically preferably trimethylsilyl.

[0053] The present invention does not specifically limit the value of n in Formula III.

[0054] In the present invention, the structure of the polytheanine includes, but is not limited to, homopolymers, diblock polymers, triblock polymers, multiblock polymers, random polymers, star polymers, cyclic polymers, and graft polymers. In the present invention, the star polymer extends multiple linear polymer chain arms (three or more) from a central core, similar to the radial structure of a star. In the present invention, the cyclic polymer is a polymer with a closed-loop structure formed by connecting the head and tail of the main chain without free chain ends. In the present invention, the graft polymer consists of a main chain and multiple side chains (graft chains), and the side chains are connected to the main chain in the form of "branches".

[0055] In the present invention, the polytheanine may have optical isomers, including: L-type, D-type, and racemic mixture (DL type).

[0056] The present invention also provides a method for preparing the polytheanine according to the above technical solution, including the following steps: Mix the polymerization monomer, initiator, and polar solvent of the polytheanine, and carry out a polymerization reaction to obtain the polytheanine; The polymerization monomer of the polytheanine is the polymerization monomer of the polytheanine according to the above technical solution; The initiator is one or more of aliphatic primary amines, aliphatic secondary amines, benzylamine, silylamine, polyamino acids, polyetheramines, or polyamides.

[0057] In the present invention, the aliphatic primary amines preferably include methylamine, ethylamine, n-propylamine, n-butylamine, neopentylamine, or n-hexylamine.

[0058] In the present invention, when the initiator is an aliphatic primary amine, in the formula III, R1 is an alkyl group and R2 is hydrogen. Taking n-butylamine as an example, the specific structure is as follows: .

[0059] In the present invention, when the initiator is n-butylamine with the above structure, in the formula III, R1 is a n-butyl group and R2 is hydrogen.

[0060] In the present invention, the aliphatic secondary amines preferably include N-ethylmethylamine, diethylamine, N-ethyl-n-propylamine, N-ethyl-n-butylamine, N-ethylneopentylamine, or N-ethyl-n-hexylamine.

[0061] In the present invention, when the initiator is an aliphatic secondary amine, in the formula III, R1 is an alkyl group and R2 is a C1-C8 alkyl group. Taking diethylamine as an example, the specific structure is as follows: .

[0062] In the present invention, when the initiator is diethylamine with the above structure, in the formula III, both R1 and R2 are ethyl groups.

[0063] In the present invention, the benzylamine has the following structure: .

[0064] In the present invention, when the initiator is the benzylamine having the above structure, in Formula III, R1 is benzyl and R2 is hydrogen.

[0065] In the present invention, the silylamine has the following structure: .

[0066] In the present invention, when the initiator is the silylamine having the above structure, in Formula III, both R1 and R2 are trimethylsilyl.

[0067] In the present invention, the polyamino acid preferably specifically includes poly(sarcosine).

[0068] In the present invention, when the initiator is a polyamino acid, in III, R1 is a polyamino acid chain and R2 is hydrogen or a C1-C8 alkyl group. Taking poly(sarcosine) as an example, the specific structure is as follows: .

[0069] In the present invention, when the initiator is poly(sarcosine) having the above structure, in Formula III, R1 is a poly(sarcosine) chain and R2 is methyl.

[0070] In the present invention, when the initiator is a polyetheramine, in III, R1 is a polyether chain and R2 is hydrogen or a C1-C8 alkyl group. Taking polyethylene glycol amine as an example, the specific structure is as follows: .

[0071] In the present invention, when the initiator is polyethylene glycol amine having the above structure, in Formula III, R1 is a polyether chain and R2 is hydrogen.

[0072] In the present invention, when the initiator is a polyamide, in III, R1 is a polyamide chain and R2 is hydrogen or a C1-C8 alkyl group. Taking polyamide-6 (nylon 6) as an example, the specific structure is as follows: .

[0073] In the present invention, when the initiator is polyamide-6 having the above structure, in Formula III, R1 is a polyamide chain and R2 is hydrogen.

[0074] In the present invention, the molar ratio of the polymerization monomer of the theaamino acid to the initiator is preferably 5 to 200:1, more preferably 10 to 100:1, and specifically preferably 5:1, 10:1, 20:1, 25:1, 30:1, 40:1, 50:1, 60:1, 70:1, 80:1, 90:1, 100:1, 110:1, 120:1, 130:1, 140:1, 150:1, 160:1, 170:1, 180:1, 190:1 or 200:1.

[0075] In the present invention, the polar solvent preferably includes one or more of dioxane, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, sulfolane, acetonitrile, benzonitrile, dichloromethane, dichloroethane, chloroform, toluene, acetone, methanol, ethanol, ethylene glycol and water. More preferably, it is a mixed solvent of acetonitrile and water. In the mixed solvent of acetonitrile and water, the volume ratio of acetonitrile to water is preferably 2:1.

[0076] In the present invention, the mixing of the polymerization monomer, initiator and polar solvent of the theaamino acid preferably includes the following steps: dissolving the polymerization monomer of the theaamino acid in the polar solvent, and then adding the polar solvent solution of the initiator.

[0077] In the present invention, the temperature of the polymerization reaction is preferably 20 to 100 °C, specifically preferably 20 °C, 30 °C, 40 °C, 45 °C, 50 °C, 60 °C, 70 °C, 80 °C, 90 °C or 100 °C; the time is preferably 0.5 to 72 h, specifically preferably 0.5 h, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 12 h, 18 h, 24 h, 36 h, 48 h, 60 h or 72 h. In the present invention, the polymerization reaction is preferably carried out under the condition of an oil bath.

[0078] After the polymerization reaction, the present invention preferably further includes post-treatment. In the present invention, when the polymerization monomer of the theanine is the structure shown in Formula I, the post-treatment preferably includes: performing a first precipitation on the obtained polymerization reaction liquid, and collecting the oily substance; redissolving the oily substance and then performing a second precipitation, and collecting the precipitate for drying to obtain theanine. In the present invention, the reagent for the first precipitation is preferably acetonitrile. In the present invention, the reagent for redissolving is preferably ethanol. In the present invention, the reagent for the second precipitation is preferably ethyl acetate. In the present invention, the drying is preferably vacuum drying, and the present invention does not specifically limit the parameters of the vacuum drying. In the present invention, when the polymerization monomer of the theanine is the structure shown in Formula II, the post-treatment preferably includes: performing a third precipitation on the obtained polymerization reaction liquid, and collecting the precipitate for drying to obtain theanine. In the present invention, the reagent for the third precipitation is preferably ether. In the present invention, the drying is preferably vacuum drying, and the present invention does not specifically limit the parameters of the vacuum drying.

[0079] The following examples are used to illustrate in detail the polymerization monomers of theanine provided by the present invention, their preparation methods, theanine and its derivatives and their preparation methods, but they should not be construed as limiting the protection scope of the present invention.

[0080] In the following examples, the polymer molecular weight ( M n ), and the molecular weight distribution ( Ð ) were determined by gel permeation chromatography (SEC). The system includes a Waters 1515 liquid chromatography pump, a Waters 2414 differential refractive index indicator, and two Shodex KF columns. The mobile phase is hexafluoroisopropanol (containing 3 mg / mL potassium trifluoroacetate), the flow rate is 0.8 mL / min, and the column temperature is 40 °C. The standard curve was calibrated with narrow-distribution polymethyl methacrylate (PMMA) as the standard sample.

[0081] Proton nuclear magnetic resonance ( 1 H NMR) and carbon nuclear magnetic resonance ( 13 C NMR) were collected on a Bruker Avance DMX 400 nuclear magnetic resonance spectrometer, using deuterated dimethyl sulfoxide (DMSO- d 6) as the deuterated reagent and tetramethylsilane (TMS) as the internal standard.

[0082] In the examples, S -ethoxycarbonylthioacetic acid and various initiators are all commercially available products.

[0083] Example 1: Preparation of the -NTA monomer L-theanine (17.4 g, 0.1 mol) andS (18.0 g, 0.1 mol) of ethylthiocarbonyl mercaptoacetic acid was dissolved in deionized water, and sodium hydroxide (8.0 g, 0.2 mol) was slowly added under an ice-water bath. After stirring well to completely dissolve it, the reaction was carried out at room temperature for 72 h. After the reaction was completed, concentrated hydrochloric acid was used to adjust the pH of the reaction solution to about 1 to obtain an acidified solution. The acidified solution was extracted with ethyl acetate. After combining the organic phases, the organic phase was washed with a 5 wt% aqueous citric acid solution, and then dried over anhydrous sodium sulfate. The dried organic phase was concentrated by rotary evaporation to obtain a concentrated solution, which was 27.1 g of the N-ethylthiocarbonyl theanine intermediate with a yield of >99%.

[0084] Based on 0.1 mol of the N-ethylthiocarbonyl theanine intermediate, the obtained concentrated solution was dissolved in ethyl acetate, and phosphorus tribromide (32.5 g, 0.12 mol) was slowly added dropwise under an ice-water bath. The reaction system was continued to react at room temperature for 3 h. After the reaction was completed, saturated brine was added to the system for extraction, and the organic phase was collected. Then the organic phase was washed with a saturated aqueous sodium bicarbonate solution, and the washed organic phase was dried over anhydrous sodium sulfate and concentrated by rotary evaporation to obtain a crude product. The crude product was recrystallized from a mixed solvent of ethyl acetate / n-hexane (the volume ratio of ethyl acetate to n-hexane was 1:1) to obtain 10.9 g of a white solid, which was The-NTA with a yield of 50.5%.

[0085] The-NTA's 1 The H NMR spectrum is as Figure 1 shown 1 H NMR (400 MHz, DMSO- d 6) δ: 0.99 (t, 3H), 1.78 - 2.05 (m, 2H), 2.05 - 2.31 (m, 2H), 3.04 (q, 2H), 4.59 (d, 1H), 7.85 (t, 1H), 9.31 (s, 1H) ppm.

[0086] Example 2: Preparation of The-NPC monomer Dissolve L-theanine (17.4 g, 0.1 mol) and sodium bicarbonate (25.2 g, 0.3 mol) in 150 mL of deionized water. Add 150 mL of methyl tert-butyl ether to this solution, and then slowly dropwise add phenyl chloroformate (15.6 g, 0.1 mol) under an ice-water bath; the reaction system is stirred at 30 °C for 3 h. After the reaction is completed, the aqueous phase is washed with methyl tert-butyl ether to remove the by-product phenol, and then the washed aqueous phase is acidified with hydrochloric acid to obtain an acidified solution; the target product in the acidified solution is extracted with ethyl acetate, the organic phases are combined, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation to obtain a crude product; the crude product is recrystallized from a mixed solvent of ethyl acetate / n-hexane (the volume ratio of ethyl acetate to n-hexane is 1:2) to obtain 26.2 g of a white solid, which is The-NPC, with a yield of 89%.

[0087] The 1 H NMR spectrum of -NPC is as Figure 2 shown 1 H NMR (400 MHz, DMSO- d 6) δ: 1.00 (t, 3H), 1.69 - 2.13 (m, 2H), 2.20 (m, 2H), 3.06 (q, 2H), 3.82 - 4.17 (m, 1H), 6.98 - 7.46 (m, 5H), 7.84 (t, 1H), 8.09 (d, 1H), 12.71 (s, 1H) ppm.

[0088] Example 3: Preparation of linear polyamino acid (poly-L-theanine) Weigh The-NTA (0.3249 g, 1.5024 mmol) obtained in Example 1 and dissolve it in a mixed solvent of 1.6 mL of acetonitrile and water, and then add 0.31 mL of an acetonitrile solution of benzylamine (0.0982 mol / L, 0.0304 mmol). The final volume ratio of acetonitrile to water in the reaction system is 2:1, and the molar ratio of The-NTA to benzylamine is 50:1. Place the reaction system in an oil bath at 45 °C and react for 4 h. After the reaction is completed, pour the reaction solution into acetonitrile to precipitate an oil. Then dissolve the oil in a small amount of ethanol, and then pour it into ethyl acetate for precipitation. The obtained polymer is dried in vacuo to obtain 0.159 g of poly-L-theanine, with a yield of 67%.

[0089] After testing, the number-average molecular weight of the poly-L-theanine prepared in this example by SEC is 6.4 kg / mol, and the molecular weight distribution is 1.19. The 1 H NMR spectrum of poly-L-theanine is as Figure 3 shown.

[0090] The poly-L-theanine obtained in this example is soluble in water, and its solubility at room temperature is 15 g / 100 g of water.

[0091] Example 4: Preparation of linear polyamino acid (polyl-theanine) The preparation method was the same as that of Example 3, except that the molar ratio of The-NTA monomer to benzylamine was 25:1, and 0.161 g of polyl-theanine was obtained with a yield of 68%.

[0092] It was tested that the number-average molecular weight of the polyl-theanine prepared in this example by SEC was 3.7 kg / mol, and the molecular weight distribution was 1.19.

[0093] The optical photograph of the polyl-theanine aqueous solution (150 mg / mL) is as Figure 4 shown. It can be seen from Figure 4 that: polyl-theanine can be stably dissolved in water at this concentration to form a homogeneous and transparent solution, indicating its good water solubility and dispersibility.

[0094] Example 5: Preparation of linear polyamino acid (polyl-theanine) The preparation method was the same as that of Example 3, except that the solvent was N,N-dimethylacetamide and the reaction time was 24 h, and 0.135 g of polyl-theanine was obtained with a yield of 57%.

[0095] It was tested that the number-average molecular weight of the polyl-theanine prepared in this example by SEC was 2.5 kg / mol, and the molecular weight distribution was 1.31.

[0096] Example 6: Preparation of linear polyamino acid (polyl-theanine) The preparation method was the same as that of Example 3, except that the reaction condition was an oil bath reaction at 30 °C for 12 h, and 0.147 g of polyl-theanine was obtained with a yield of 62%.

[0097] It was tested that the number-average molecular weight of the polyl-theanine prepared in this example by SEC was 4.7 kg / mol, and the molecular weight distribution was 1.17.

[0098] Example 7: Preparation of linear polyamino acid (polyl-theanine) Weighed 0.3404 g (1.1566 mmol) of The-NPC obtained in Example 2 and dissolved it in 1.65 mL of N,N-dimethylacetamide, and then added 0.66 mL of the N,N-dimethylacetamide solution of benzylamine (0.0878 mol / L, 0.0579 mmol). The molar ratio of The-NPC to benzylamine was 20:1. After sealing the reaction system, it was placed in an oil bath at 70 °C for 24 h. After the reaction, the polymerization solution was poured into ether for precipitation, and the obtained polymer was dried in vacuo to obtain 0.125 g of polyl-theanine with a yield of 67%.

[0099] After testing, the SEC number-average molecular weight of the theanine prepared in this example is 1.9 kg / mol, and the molecular weight distribution is 1.15.

[0100] Example 8: Preparation of linear polyamino acid (theanine) The preparation method is the same as that of Example 7, except that the solvent is dimethyl sulfoxide, and 0.132 g of theanine is obtained, with a yield of 71%.

[0101] After testing, the SEC number-average molecular weight of the theanine prepared in this example is 2.1 kg / mol, and the molecular weight distribution is 1.15.

[0102] Example 9: Preparation of diblock copolymer - linear polyamino acid (poly(sarcosine)- b -theanine) Weigh the The-NTA obtained in Example 1 (0.2359 g, 1.0908 mmol) and dissolve it in 0.7 mL of water, then add 1.4 mL of an acetonitrile solution of poly(sarcosine) (the number-average molecular weight of poly(sarcosine) is 4.0 kg / mol, 0.1744 g, 0.0436 mmol). The molar ratio of The-NTA to poly(sarcosine) is 25:1. Place the reaction system in an oil bath at 45 °C and react for 12 h. After the reaction is completed, pour the reaction solution into acetonitrile to precipitate an oily substance. Then dissolve the oily substance in a small amount of ethanol, and then pour it into ethyl acetate for precipitation. The obtained polymer is dried in vacuo to obtain poly(sarcosine)- b -theanine, with a yield of 0.212 g and a yield of 61%.

[0103] After testing, the SEC number-average molecular weight of the poly(sarcosine)- b -theanine prepared in this example is 14.1 kg / mol, and the molecular weight distribution is 1.28. The b H NMR spectrum of poly(sarcosine)- 1 is as shown in Figure 5 the figure.

[0104] The above are only the preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and modifications can be made, and these improvements and modifications should also be regarded as the protection scope of the present invention.

Claims

1. A polymerization monomer of polytheanine, characterized in that, Having the structure shown in Formula I or Formula II: Formula I, Formula II.

2. The preparation method of the polymerization monomer of the polytheanine according to claim 1, characterized in that, The preparation method of the structure shown in Formula I includes the following steps: Mix L-theanine, S-ethoxycarbonylmercaptoacetic acid, a base, and water, and carry out a nucleophilic substitution reaction to obtain an N-ethoxycarbonyltheanine intermediate; The N-ethoxycarbonyltheanine intermediate undergoes a ring-closing reaction under the condition of phosphorus tribromide to obtain the structure shown in Formula I; The preparation method of the structure shown in Formula II includes the following steps: L-theanine, phenyl chloroformate, and sodium bicarbonate undergo an elimination reaction in a two-phase mixed solvent to obtain the structure shown in Formula II; the two-phase mixed solvent includes water and an organic solvent.

3. The preparation method according to claim 2, characterized in that, During the nucleophilic substitution reaction, the theanine is L-theanine; the base includes one or more of inorganic bases and / or organic bases; The inorganic base includes sodium hydroxide and / or potassium hydroxide; The organic base includes one or more of sodium alkoxide, potassium alkoxide, and tetraalkylammonium hydroxide; The number of carbon atoms of the sodium alkoxide and potassium alkoxide is independently 1-4; The number of carbon atoms of the alkyl group in the tetraalkylammonium hydroxide is 2-8; The molar ratio of theanine to S-ethoxycarbonylmercaptoacetic acid is 1-2:1, and the molar ratio of theanine to the base is 1:2-4; The time of the nucleophilic substitution reaction is 12-120 h.

4. The preparation method according to claim 2 or 3, characterized in that, During the ring-closing reaction, the molar ratio of the N-ethoxycarbonyltheanine intermediate to phosphorus tribromide is 1:1-3, and the time of the ring-closing reaction is 0.5-24 h.

5. The preparation method according to claim 2, wherein During the elimination reaction, the theanine is L-theanine, the molar ratio of theanine to phenyl chloroformate is 2:1-1:2, and the molar ratio of theanine to sodium bicarbonate is 1:2-4; The organic solvent includes one or more of methyl tert-butyl ether, diethyl ether, ethyl acetate, dichloromethane, dichloroethane, and chloroform; The volume ratio of water to the organic solvent in the two-phase mixed solvent is 2:1-1:2; the temperature of the elimination reaction is 15-35 °C, and the time is 3-24 h.

6. A polytheanine, characterized in that, Having the structure shown in Formula III: Formula III; In Formula III, R1 is one or more of an alkyl group, a benzyl group, a silicon group, a polyamino acid chain, a polyether chain, or a polyamide chain; R2 is hydrogen, a silicon group, or a C1-C8 alkyl group; R3 is hydrogen.

7. The preparation method of the polytheanine according to claim 6, characterized in that, Including the following steps: Mix the polymerization monomer of polytheanine, an initiator, and a polar solvent, and carry out a polymerization reaction to obtain the polytheanine; The polymerization monomer of the polytheanine is the polymerization monomer of the polytheanine as claimed in claim 1; The initiator is one or more of a primary aliphatic amine, a secondary aliphatic amine, benzylamine, silamine, polyamino acid, polyetheramine, or polyamide.

8. The preparation method according to claim 7, characterized in that, The molar ratio of the polymerization monomer of the polytheanine to the initiator is 5-200:

1.

9. The preparation method according to claim 7, characterized in that, The polar solvent includes one or more of dioxane, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, sulfolane, acetonitrile, benzonitrile, dichloromethane, dichloroethane, chloroform, toluene, acetone, methanol, ethanol, ethylene glycol, and water.

10. The preparation method according to claim 7, characterized in that, The temperature of the polymerization reaction is 20-100 °C, and the time is 0.5-72 h.

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